De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.
De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies.
复制标题
DOI：
10.1016/j.ajhg.2016.12.012
复制
发表时间：
2014-10-02
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
作者：
新出现的证据表明，癫痫性脑病在遗传上是高度异质性的，这强调了需要大量特征良好的个体来进一步确定遗传格局。通过两个联盟（EuroEPINOMICS和Epi 4K/EPGP）之间的合作，我们分析了356个具有“经典”癫痫性脑病、婴儿痉挛和伦诺克斯Gastaut综合征的三联体的外显子组测序数据，包括先前由Epi 4K/EPGP联盟分析的264个三联体。在这个扩展的队列中，我们发现了429个新生突变，包括5个个体中的DNM 1的新生突变和2个个体中的GABBR 2，FXR和RYR 3的新生突变。与以前的研究不同，该队列足够大，使用似然分析（p = 8.2* 10（-4））显示与一般人群相比，癫痫脑病先证者中的新生突变显著过量，支持新生突变在癫痫脑病中的突出作用。我们带来的统计证据表明，DNM 1突变会导致癫痫性脑病，发现了另外三个基因作用的暗示性证据，并表明至少12%的分析个体具有可识别的因果性从头突变。引人注目的是，这些先证者中75%的突变被预测会破坏参与调节突触传递的蛋白质，并且在整个队列中，该途径中的基因中的从头突变也显著富集。这些发现强调了突触失调在癫痫性脑病中的重要作用，超过了离子通道功能障碍所引起的作用。
Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the "classical" epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2* 10(-4)), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.